Project Summary Candidate: Rachel Knipe, MD is a physician in the Division of Pulmonary and Critical Care at Massachusetts General Hospital (MGH) and an Instructor of Medicine at Harvard Medical School (HMS). She has developed expertise in cell and molecular biology and murine modeling of pulmonary fibrosis, focusing on the role of ROCK, S1P1 and the actin cytoskeleton in fibrogenesis. This K08 application aims to understand the role of vascular permeability in the development of pulmonary fibrosis, studying two opposing regulators of permeability, ROCK and S1P1. Her short-term goals are to obtain training in endothelial biology, animal modeling of human lung disease, micro-engineered culture systems, and translational research. Her long term goal is to lead a translational research program on vascular permeability and pulmonary fibrosis. The experiments, training, and mentoring plan outlined in this proposal will successfully position Dr. Knipe for her first R01 and an independent career as a physician-scientist. Mentorship, Training Activities and Environment: Dr. Knipe will perform the work outlined in this proposal in the Division of Pulmonary and Critical Care Medicine under the mentorship of Drs. Benjamin Medoff and Andrew Luster. Drs. Medoff and Luster both have extensive experience in mouse modeling of lung disease and translational research and excellent records of mentoring. Drs. James Liao, Timothy Hla, Christopher Chen and Barry Shea will serve on Dr. Knipe's advisory committee and provide expertise in ROCK and S1P1 signaling, mouse modeling of lung disease, cellular biology utilizing advanced micro-engineered culture systems and translational research. Dr. Knipe will complete courses in endothelial biology, mouse modeling of human lung disease, tissue engineering, and translational research through Harvard Medical School and Harvard University. Research: Idiopathic Pulmonary Fibrosis (IPF) is a progressive scarring lung disease that very often leads to respiratory failure. There remains a large unmet need for effective therapies. IPF is thought to be driven by dysfunctional wound healing responses to repetitive tissue injury. Increased vascular permeability is a cardinal wound healing response, which in the lung allows plasma proteins to leak from the pulmonary vasculature into the airspaces. Increased permeability has been shown in the lungs of IPF patients, and predicts mortality. We propose that restoring endothelial barrier function after lung injury, either by inhibiting endothelial cell ROCK activation or augmenting endothelial cell S1P1 activation, could provide a novel and specific therapeutic strategy to attenuate the development of pulmonary fibrosis.